Antipsychotic agents

ABSTRACT

Fluoromethyl fluoropropyl ethers, e.g. CHF 2  --O--CH 2  CF 2  CF 3  and CHF 2  --O--CF 2  CHFCF 3 , useful for antipsychotic treatment by inhalation sufficient to induce therapeutic convulsions.

This is a division of Ser. No. 373,547, filed June 25, 1973, nowabandoned.

This invention relates to certain fluoromethyl fluoropropyl ethers whichare useful as convulsant agents. These agents may be administered byinhalation to provide an alternative to electroconvulsive therapy for asevere depression in a patient who presents an immediate risk ofsuicide, or a depression that has proved refractory to treatment with anantidepressant drug. Convulsive therapy with these agents also is usefulin schizoaffective reactions, especially those with attendantdepression, and in acute schizophrenic reactions with excitement or withcatatonic withdrawal. The depth and duration of convulsions produced byan inhalant agent is comparatively easy to control, the outset ofconvulsions is more gradual, the clonic phase tends to last longer, andusually patients express a preference for inhaloconvulsive toelectroconvulsive therapy. Consequently, the convulsant agents of thisinvention provide a practical advantage to antipsychotic therapy.

The convulsant agents of this invention are methyl propyl etherscontaining 6-8 fluorine substituents with 1 to 2 fluorines on the methylmoiety and 4 to 6 fluorines on the propyl moiety. They can be describedby the following structural formulas:

CHF₂ --O--CH₂ CF₂ CHF₂ (I)⁴, CHF₂ --O--CH₂ CF₂ CF₃ (II), CHF₂ --O--CF₂CHFCF₃ (III), CHF₂ --O--CF(CHF₂)₂ (IV)², and CH₂ F--O--CH₂ CF₂ CF₃ (V)¹

The preferred convulsant agents of this invention are the ethers I, II,III and IV, which are more stable than V to heat.

The convulsant agents I-V of this invention have each been been found tobe at least 6 times less lethal than either the closely related knownconvulsant³, CF₃ --O--CH₂ CF₂ CHF₂ (VI) or the well known usefulconvulsant flurothyl⁵, CF₃ CH₂ --O--CH₂ CF₃ (VII) in mice (See Table 1).

Another advantage of the convulsant agents of this invention is that thevapor concentrations at which they are convulsant are comparatively easyto control and administer using conventional "anesthetic machines".

It is most surprising that the ethers I-V are convulsant agents, sincenine closely related fluoromethyl fluoropropyl ethers containing 6 to 8fluorine substituents were tested and found to be nonconvulsant in mice;4 of these were tested and also found to be nonconvulsant in dogs. (SeeTable 2)

It is further surprising that the ethers I-V are convulsant agents,since seven related methyl fluoropropyl ethers containing 4 to 7fluorine substituents were found to be nonconvulsant in mice, and one ofthese has even been shown to be antagonistic to flurothyl inducedconvulsions⁵. (See Table 3)

The fluorinated ethers in Tables 1, 2 and 3 were tested by exposing maleCF-1 mice to a minimum of three graded concentrations of the testcompound admixed with air for 5 minutes in a manner similar to thatreported by Robbins.¹⁴ Thirty mice in groups of five in a covered 6.3liter animal jar were observed for convulsions, anesthesias and othereffects. If anesthesia occurred, the median anesthetic concentration(AC₅₀) was established. Another thirty mice were treated similarly toestablish the median lethal concentration (LC₅₀). The concentrationswere calculated from the volume used and density of the test compoundand the volume of air (6.31) in the test jar using the ideal gas law.The results for the convulsant ethers are given in Table 1; Tables 2 and3 contain the results for related nonconvulsant ethers, most of whichare good anesthetic agents.

The convulsant agents I-V are colorless, volatile liquids boilingbetween 46°C and 76°C with not unpleasant odors and are nonflammable inair.

The ethers I and II can be prepared from 2,2,3,3-tetrafluoropropanol and2,2,3,3,3-pentafluoropropanol, respectively, and chlorodifluoromethanewith sodium or potassium hydroxide, e.g., in the manner described inU.S. Pat. No. 3,689,459. (See Examples 1 and 2)

The ether III can be prepared from methyl 1,1,2,3,3,3-hexafluoropropylether and two molar equivalents of chlorine at 15°-25°C with ultravioletirradiation to give the dichloromethyl 1,1,2,3,3,3-hexafluoropropylether (XXIV),

    chcl.sub.2 --O--CF.sub.2 CHFCF.sub.3                       XXIV

which can be treated with about a 0.67 molar equivalent of brominetrifluoride at 0°-25°C to give the ether III. (See Examples 3 and 4)

The ether IV can be prepared from1,3-dichloro-1,1,2,3,3-pentafluoro-2-propyl methyl ether and two molarequivalents of chlorine at 15°-25°C with ultraviolet irradiation to givethe dichloromethyl 1,3-dichloro-1,1,2,3,3-pentafluoro-2-propyl ether(XXV),

    chcl.sub.2 --O--CF(CF.sub.2 Cl).sub.2                      XXV

which can be treated with about one molar equivalent of antimonytrifluoride and about 0.02 molar equivalent of antimony pentachloride at60°-90°C to give the 1,3-dichloro-1,1,2,3,3-pentafluoro-2-propyldifluoromethyl ether XXVI,

    chf.sub.2 --o--cf(cf.sub.2 cl).sub.2                       XXVI

which can, in turn, be treated at about 25°C with a 0.55 molarequivalent of lithium aluminum hydride as a 0.9 molar solution indiethylene glycol diethyl ether to give the ether IV. (See Examples 5, 6and 7)

The ether V can be prepared by a method analogous to that described byWeinmayr¹, or from methyl 2,2,3,3,3-pentafluoropropyl ether and onemolar equivalent of sulfuryl chloride at 0°-35°C with ultravioletirradiation to give the chloromethyl 2,2,3,3,3-pentafluoropropyl etherXXVII,

    ch.sub.2 cl--O--CH.sub.2 CF.sub.2 CF.sub.3                 XXVII

which can be treated with about a 0.4 molar equivalent of brominetrifluoride at -5°C to give the ether V (See Examples 8 and 9). It wasfound that the ether V was unstable to heat and decomposed with theformation of hydrogen fluoride upon distillation at 760 torr; however,it was stable to 70°C in the presence of an alkaline material, e.g.,soda lime.

Although specific methods of preparing the convulsant agents of thisinvention are described herein, it will be appreciated that theinvention is not limited to these specific methods of preparation.

The following examples will further illustrate the present invention butit will be understood that the invention is not limited to theseexamples.

EXAMPLES Example 1

Difluoromethyl 2,2,3,3-tetrafluoropropyl ether (I)

The ether I was prepared and identified according to the procedure ofExample 1 of U.S. Pat. No. 3,689,459, which is incorporated herein byreference.

Example 2

Difluoromethyl 2,2,3,3,3-pentafluoropropyl ether (II)

The ether II was prepared in a manner analogous to the preparation ofthe ether I of Example 1. Fractional distillation of the crude II gaveII of 99.6% purity (by gas-liquid chromatography), b₇₆₀ 46.2°-46.3°C, d₄²² 1.46, in 44% of theory based on the amount of2,2,3,3,3-pentafluoropropanol employed. The structure of II wasconfirmed by proton NMR spectroscopy.

Example 3

Dichloromethyl 1,1,2,3,3,3-hexafluoropropyl ether (XXIV)

Methyl 1,1,2,3,3,3-hexafluoropropyl ether was stirred at 15°-25°C andirradiated with ultraviolet light as two molar equivalents of chlorinegas was added slowly. Analysis by GLC showed the product to be 76% XXIV,15% CCl₃ --O--CF₂ CHFCF₃ and 8% CH₂ Cl--O--CF₂ CHFCF₃. Fractionationaldistillations of this product gave XXIV of 99.7% by GLC, b₇₆₀98.1°-98.4°C. The structure of XXIV was confirmed by proton NMRspectroscopy.

Example 4

Difluoromethyl 1,1,2,3,3,3-hexafluoropropyl ether (III)

The ether XXIV of 97.9% purity (284 g, 1.13 moles) was stirred and keptbetween 0°-10°C as bromine trifluoride (102 g, 0.746 mole) was addeddropwise. Before the reaction was complete, it was stopped by thecautious addition of ice to decompose the remaining BrF₃. Then colddilute sodium hydroxide solution was added to remove halogens and acids.The organic layer was separated, washed with water and dried; weight 219g. Analyses by GLC and proton NMR showed this product to be 66% III and31% CHFCl--O--CF₂ CHFCF₃. Fractional distillation gave III of 99.9%purity, b₇₆₀ 47.0°-47.3°C; d₄ ²³ 1.536; weight 113 g as well asCHFCl--O--CF₂ CHFCF₃ of 97.6% purity, b₇₆₀ 69.9°-70.3°C. Both structureswere confirmed by proton NMR spectroscopy.

Example 5

Dichloromethyl 1,3-dichloro-1,1,2,3,3-pentafluoro-2-propyl ether (XXV)

1,3-Dichloro-1,1,2,3,3-pentafluoro-2-propyl methyl ether (303 g, 1.3moles), b₇₆₀ 96.2°-97.3°C, was chlorinated by addition of chlorine gas(193 g, 2.72 moles) at 15°-25°C with the aid of ultraviolet irradiation.The product was freed of hydrogen chloride, dried and fractionallydistilled at 45 torr to give XXV, b₄₅ 67.2°-69.3°C, in 80% of thetheoretical yield.

Example 6

Difluoromethyl 1,3-dichloro-1,1,2,3,3-pentafluoro-2-propyl ether (XXVI)

The ether XXV (296 g, 0.97 mole) and substantially anhydrous antimonytrifluoride (185 g, 1.04 mole) were stirred at 60°C and antimonypentachloride (5.0 g, 0.017 mole) was added slowly. This mixture washeated to the reflux point at atmospheric pressure for 2 hours; then theproduct was distilled from the antimony halides at atmospheric pressure.The distillate was condensed, washed with acidified water then withneutral water, dried and fractionally distilled to give XXVI, b₇₆₀83.6°-84.1°C, in 90% of the theoretical yield.

Example 7

Difluoromethyl 1,1,2,3,3-pentafluoro-2-propyl ether (IV)

The ether XXVI (213 g, 0.79 mole) at 25°C was stirred as 0.9 M lithiumaluminum hydride in diethylene glycol diethyl ether (484 ml, 0.436 moleof Li Al H₄) was added dropwise. Then the product was distilled atatmospheric pressure through a cold water condensor into an ice cooledreceiver until 157 g of IV was collected. This distillate wasfractionally distilled to give IV, b₇₆₀ 68.1°-68.2°C, of 99.7% purity(by gas-liquid chromatography) in 93% of the theoretical yield; densityat 23°C was 1.554. The structure of IV was confirmed by proton NMRspectroscopy.

EXAMPLE 8

Chloromethyl 2,2,3,3,3-pentafluoropropyl ether (XXVII)

Methyl 2,2,3,3,3-pentafluoropropyl ether (225g, 1.37 mole) in a flaskfitted with a dry ice cooled condensor and moisture trap was stirred,heated to 33°C, irradiated with ultraviolet light, and sulfuryl chloride(174 g, 1.29 mole) was added dropwise. The reaction temperature droppedto about 0°C as SO₂ returned from the condensor. The condensor wasallowed to warm gradually to permit SO₂ to escape and the reactiontemperature to rise to about 33°C to complete the chlorination. Theproduct was washed with ice cold water then with dilute sodium hydroxidesolution to remove SO₂ and dried to give 250 g of crude XXVII. This wasfractionally distilled to give XXVII, b₇₆₀ 87.1-88.5; yield 159 g,purity 92% by GLC. The structure of XXVII was confirmed by proton NMRspectroscopy.

Example 9

Fluoromehtyl 2,2,3,3,3-pentafluoropropyl ether (V)

The ether XXVII was refractionated to obtain a sample (56.8 g, 0.286mole) of <99% purity by GLC. This sample was cooled to -5°C and stirredin a teflon bottle as bromine trifluoride (15.6 g, 0.114 mole) was addeddropwise. The product was stirred with ice and dilute sodium hydroxidesolution to remove halogens and acids, separated, washed with distilledwater, freeze-dried at -20°C and then dried at 0°C over type 3Amolecular sieve. The V so obtained was 99.0% by GLC; micro b₇₆₀ 62.2°C;d₄ ² 1.41; yield 45 g (87% of theory). The molecular sieve type 3A ismanufactured and sold by the Linde Division of Union Carbide Company.

                                      TABLE 1                                     __________________________________________________________________________    CONVULSANT FLUOROMETHYL FLUOROPROPYL ETHERS                                                      MOUSE    MOUSE                                             COMPOUND       B.sub.760                                                                         CONVULSANT                                                                             LC.sub.50                                                                              ADDITIONAL REMARKS                                      C   CONC., VOL. %                                                                          VOL. %                                            __________________________________________________________________________    I. CHF.sub.2 -O-CH.sub.2 CF.sub.2 CHF.sub.2.sup.4                                            76      1.0    3.2                                                                              CLONIC CONVULSIONS                           II.                                                                              CHF.sub.2 -O-CH.sub.2 CF.sub.2 CF.sub.3                                                   46      1.4  > 4.2                                                                              CLONIC AND TONIC CONVULSIONS, CATALEPSY      III.                                                                             CHF.sub.2 -O-CF.sub.2 CHFCF.sub.3                                                         47      2.0  > 12                                              IV.                                                                              CHF.sub.2 -O-CF(CHF.sub.2).sub.2.sup.2                                                    68      1.2    5.3                                                                              CONVULSIONS AND SEDATION; OPISTHOTONOID                                       CONV. IN DOGS                                V. CH.sub.2 F-O-CH.sub.2 CF.sub.2 CF.sub.3.sup.1                                             62      1.5  > 3.0                                                                              METRAZOLE-LIKE CONVULSIONS                   VI.                                                                              CF.sub.3 -O-CH.sub.2 CF.sub.2 CHF.sub.2.sup.3                                             45.5                                                                              ≦                                                                          0.5  ≦                                                                        0.5                                                                              "VIOLENT CONVULSIONS AND DEATH IN 30-120                                      SEC.".sup.3                                  VII.                                                                             CF.sub.3 -CH.sub.2 -O-CH.sub.2 CF.sub.3                                                   64  ≦                                                                          0.25.sup.5                                                                         < 0.50.sup.5                                                                       CLONIC AND TONIC CONVULSIONS IN 30           __________________________________________________________________________                                     SEC.                                          .sup.1 WEINMAYR, U.S. PATENT 2,992,276.                                       .sup.2 REGAN AND ZIMMERMAN, FED. PROC. ABS., 30(2), 442(1971).?               .sup.3 ALDRICH AND SHEPPARD, J. ORG. CHEM. 29, 11-15(1964).                   .sup.4 REGAN, U.S. PATENT 3,689,459.                                          .sup.5 KRANTZ, RUDO AND LOECHER, PROC. SOC. EXP. BIOL. MED., 124,             820-2(1967).                                                             

                                      TABLE 2                                     __________________________________________________________________________    NONCONVULSANT FLUOROMETHYL FLUOROPROPYL ETHERS                                                      MOUSE MOUSE                                             COMPOUND         B.sub.760                                                                          AC.sub.50                                                                           LC.sub.50                                                                            ADDITIONAL REMARKS                                          C    VOL. %                                                                              VOL. %                                            __________________________________________________________________________    VIII.                                                                              CHF.sub.2 -O-CHFCF.sub.2 CHF.sub.2.sup.4                                                  75   0.61  6.5   NONCONVULSANT IN DOGS                       IX.  CHF.sub.2 -O-CHFCF.sub.2 CF.sub.3                                                         44.5 4.3   >9.9                                              X.   CHF.sub.2 -O-CH(CF.sub.3).sub.2.sup.2,7                                                   42   2.5   12    NONCONVULSANT IN DOGS                       XI.  CHF.sub.2 -O-CH(CF.sub.3)CHF.sub.2.sup.2                                                  65.5 0.84  4.9                                               XII. CHF.sub.2 -O-CH(CHF.sub.2).sub.2.sup.2                                                    90   0.64  3.8                                               XIII.                                                                              CH.sub.2 F-O-CF.sub.2 CHFCF.sub.3                                                         69   2.1   6.4                                               XIV. CH.sub.2 F-O-CF(CF.sub.3)CHF.sub.2.sup.2                                                  64   2.5   9.0   NONCONVULSANT IN DOGS                       XV.  CH.sub.2 F-O-CH(CF.sub.3).sub.2.sup.2,6                                                   58.5 1.4   8.5   NONCONVULSANT IN DOGS                       XVI. CH.sub.2 F-O-CH(CF.sub.3)CHF.sub.2.sup.2                                                  78.5 0.84  5.1                                               __________________________________________________________________________     .sup.6 REGAN AND LONGSTREET, U.S. PATENT 3,683,592.                           .sup.7 CROIX AND SZUR, U.S. PATENT 3,476,860.                            

                                      TABLE 3                                     __________________________________________________________________________    NONCONVULSANT METHYL FLUOROPROPYL ETHERS                                                              MOUSE MOUSE                                           COMPOUND           B.sub.760                                                                          AC.sub.50                                                                           LC.sub.50                                                                            ADDITIONAL REMARKS                                          C    VOL. %                                                                              VOL. %                                          __________________________________________________________________________    XVII. CH.sub.3 -O-CF.sub.2 CF.sub.2 CF.sub.3                                                     34   n.a..sup.15                                                                         50   DEATH DUE TO ANOXIA                        XVIII.                                                                              CH.sub.3 -O-CF.sub.2 CHFCF.sub.3.sup.9,12                                                  54   3.9   >8.0                                            XIX.  CH.sub.3 -O-CH.sub.2 CF.sub.2 CF.sub.3.sup.11                                              47.5 11    16   "EXTENSOR RIGIDITY OF HIND LEGS AND                                           TREMORS -     IN DOGS" .sup.11             XX.   CH.sub.3 -O-CH.sub.2 CF.sub.2 CHF.sub.2                                                    73   2.5   7.0                                             XXI.  CH.sub.3 -O-CH(CF.sub.3).sub.2.sup.2,5,13                                                  51   2.2   9.0  NONCONVULSANT IN DOGS; ANTAGONIST TO                                          FLUROTHYL.sup.5                            XXII. CH.sub.3 -O-CH(CF.sub.3)CHF.sub.2.sup.2                                                    61   1.5   6.9                                             XXIII.                                                                              CH.sub.3 -O-CH(CHF.sub.2).sub.2.sup.2,10                                                   82   1.4   >7.8                                            __________________________________________________________________________     .sup.8 WARNELL, U.S. PATENT 3,449,389.                                        .sup.9 RENDALL AND PEARLSON, U.S. PATENT 2,730,543.                           .sup.10 GILBERT AND VELDHUIS, U.S. PATENT 3,445,524.                          .sup.11 LU, LING AND KRANTZ, ANESTHESIOLOGY, 14, 466 (1953).                  .sup.12 DEAR AND GILBERT, U.S. APPL. (P.D. FILE 5300-1238), 12 OCTOBER        1967, SER. NO. 674,746, NOW U.S. PATENT 3,557,294.                            .sup.13 GILBERT AND VELDHUIS, U.S. PATENT 3,346,448.                          .sup.14 ROBBINS, J. PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 86,           197-204 (1946).                                                               .sup.15 NON-ANESTHETIC                                                   

Various other examples and modifications of the foregoing examples willbe apparent to those skilled in the art after reading the foregoingspecification and the appended claims without departing from the spiritand scope of the invention. All such further examples and modificationsare included within the scope of the invention as defined in thefollowing claims.

What is claimed is:
 1. The method of convulsive therapy comprisinginducing a therapeutic convulsion in an animal by administering to saidanimal an effective amount for inducing a therapeutic convulsion of thecompound CH₂ F--O--CH₂ CF₂ CF₃ in vapor form by inhalation whilemaintaining respiration of said animal.